The recent report on vitamin D from the Institute of Medicine (IOM) highlighted the need for further research to clarify the optimal levels of vitamin D for nonskeletal outcomes, including cardiovascular disease (CVD), and to assess whether the relationships vary by race/ethnicity. Observational studies have suggested interrelationships between low 25-hydroxy vitamin D [25(OH) D], high parathyroid hormone (PTH) levels, and increased risk of CVD. Vitamin D binding protein (VDBP), the major vitamin D carrier protein, plays a key role in regulating vitamin D bioavailability and could potentially be a predictor of CVD events or an effect modifier of the relation between 25(OH) D and/or PTH and CVD. Vitamin D metabolites are mostly bound to VDBP and albumin, and it is possible that the free, unbound portions of vitamin D metabolites are the most biologically active and therefore most relevant for CVD risk prediction. However, no studies have specifically assessed the association between free or bioavailable 25(OH) D levels and CVD. Available evidence on total 25(OH)D levels and cardiovascular health also remains inconsistent and inconclusive, and few studies have had sufficient size and racial/ethnic diversity to examine these relationships across a broad range of circulating 25(OH)D levels. Clearly, there is a clinical and public health need to determine whether the relationships between vitamin D biomarkers and CVD vary by race/ethnicity and whether such differences can help to explain racial/ethnic disparities in CVD risk. The Women's Health Initiative Observational Study (WHI-OS), one of the largest and most racially/ethnically diverse cohorts of postmenopausal women with comprehensive information on CVD risk factors, intermediate phenotypes, and outcomes, offers a unique and cost-effective opportunity to answer important and timely questions about racial/ethnic differences in vitamin D biomarkers with regard to CVD risk. We propose to conduct a prospective case-cohort study in the WHI-OS to assess racial/ethnic differences in the associations of total and free 25(OH)D, VDBP, and PTH levels with major cardiovascular events (a composite of nonfatal myocardial infarction [MI], nonfatal stroke, and CVD mortality). We will include all incident CVD cases in African-American (black) women (N=650) and a random sample of incident CVD cases in white women (N=1,500). Noncases will be drawn from a random subcohort of black (N=1,300) and white women (N=1,500) in the WHI-OS. In addition, we will examine whether total and free 25(OH)D, VDBP, and PTH levels correlate with a variety of intermediate CVD phenotypes, including directly measured anthropometric indices, blood pressure, lipids, and biomarkers of systemic inflammation, glycemic status, insulin resistance, insulin secretion, and renal function. In summary, the WHI-OS provides an exceptional opportunity to conduct a comprehensive evaluation of the full spectrum of variation in levels of total and free 25(OH) D, VDBP, and PTH and to examine their potential independent and joint contributions to racial/ethnic disparities in CVD risk among postmenopausal women.